1. Field of the Invention
The present invention relates to a solution polymerization process for making high molecular weight polymers containing phosphoester linkages, in particular those that degrade in vivo into non-toxic residues. The polymers made by the process of the invention are particularly useful as implantable medical devices and prolonged release drug delivery systems.
2. Description of the Prior Art
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: "Phosphorus-Containing Polymers", (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, is as follows: ##STR3## The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3 p orbitals or various 3 s-3 p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or R' group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with --O--carboxy groups may be coupled to the phosphorus via an ester bond, which is hydrolyzable. The P--O--C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
The most common general reaction in preparing poly(phosphates) is a dehydrochlorination between a phosphoro-dichloridate and a diol according to the following equation: ##STR4## Most poly(phosphonates) are also obtained by condensation between appropriately substituted dichlorides and diols.
Poly(phosphites) have been prepared from glycols in a two-stage condensation reaction. A 20% molar excess of a dimethylphosphite is used to react with the glycol, followed by the removal of the methoxyphosphonyl end groups in the oligomers by high temperature.
A Friedel-Crafts reaction can also be used to synthesize poly(phosphates). Polymerization typically is effected by reacting either bis(chloromethyl) compounds with aromatic hydrocarbons or chloromethylated diphenyl ether with triaryl phosphates. Poly(phosphates) can also be obtained by bulk condensation between phosphorus diimidazolides and aromatic diols, such as resorcinol and quinoline, usually under nitrogen or some other inert gas.
High molecular weights have generally been possible by bulk polycondensation. However, rigorous conditions are often required, which can lead to chain acidolysis (or hydrolysis if water is present). Unwanted, thermally-induced side reactions, such as cross-linking reactions, can also occur if the polymer backbone is susceptible to hydrogen atom abstraction or oxidation with subsequent macroradical recombination.
To minimize these side reactions, the polymerization can also be carried out in solution. Solution polycondensation requires that both the diol and the phosphorus component be soluble in a common solvent. Typically, a chlorinated organic solvent is used, such as chloroform, dichloromethane, or dichloroethane. The solution polymerization must be run in the presence of equimolar amounts of the reactants and a stoichiometric amount of an acid acceptor, usually a tertiary amine such as pyridine or triethylamine. The product is then typically isolated from the solution by precipitation with a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those of ordinary skill in the art, such as by washing with an aqueous acidic solution, e.g., dilute HCl.
Reaction times tend to be longer with solution polymerization than with bulk polymerization. However, because overall milder reaction conditions can be used, side reactions are minimized, and more sensitive functional groups can be incorporated into the polymer. The disadvantage of solution polymerization is that the attainment of high molecular weights, such as a molecular weight greater than about 10,000 to 20,000, is less likely.
Interfacial polycondensation can be used when high molecular weight polymers are desired at high reaction rates. Mild conditions minimize side reactions. Also the dependence of high molecular weight on stoichiometric equivalence between diol and dichloridate inherent in solution methods is removed. However, hydrolysis of the acid chloride may occur in the alkaline aqueous phase, since sensitive dichloridates that have some solubility in water are generally subject to hydrolysis rather than polymerization.
Toluene has been mentioned as a possible solvent in the solution polymerization of a variety of polymer products for a number of different reasons. For example, Kerst, U.S. Pat. No. 3,664,975 issued May 23, 1972, discloses the formation of fire-resistant polyurethane compositions by adding to the urethane-forming reaction mixture a substituted ethane diphosphonate, and toluene is mentioned as one of many different solvents that can be used when an inert liquid non-aqueous reaction medium is employed. See column 6, lines 56-61.
Okamoto et al., U.S. Pat. Nos. 4,072,658 and 4,156,663, discloses the preparation of phosphorous- and bromine-containing polymers. When the polymer is prepared by a solution polymerization, the solvents are preferably basic polar solvents, and the many examples provided of possibly useful solvents include toluene. See column 6, line 67 through column 7, line 7.
Renier et al., "Development and Characterization of a Biodegradable Polyphosphate", J. Biomed. Materials Res., 34:95-104 (1997), discloses the preparation of a biodegradable polyphosphate polymer in toluene. Specifically, poly(bisphenol A-phenylphosphate) (Mn 18 kDa, Mw/Mn=3.2) is prepared by adding phenyl phosphodichloridate to bisphenol A in the presence of triethylamine and argon gas. However, it is known that bisphenol A is an unusually active diol for polycondensations.
Accordingly, there remains a need for a polymerization procedure for more standard, less active monomer reactants that will provide significantly higher molecular weight materials than would be produced with the usual solvents employed in solution polymerization reactions, even with less active polycondensation reactants and, at the same time, minimize side-reactions.